scholarly journals A novel BMI-1 inhibitor QW24 for the treatment of stem-like colorectal cancer

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Jinhua Wang ◽  
Yajing Xing ◽  
Yingying Wang ◽  
Yundong He ◽  
Liting Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Liver Metastasis ◽  
Tumor Growth ◽  
Cell Lines ◽  
Xenograft Model ◽  
Proliferation Assay ◽  
Self Renewal ◽  
Metastasis Model

Abstract Background Cancer-initiating cell (CIC), a functionally homogeneous stem-like cell population, is resonsible for driving the tumor maintenance and metastasis, and is a source of chemotherapy and radiation-therapy resistance within tumors. Targeting CICs self-renewal has been proposed as a therapeutic goal and an effective approach to control tumor growth. BMI-1, a critical regulator of self-renewal in the maintenance of CICs, is identified as a potential target for colorectal cancer therapy. Methods Colorectal cancer stem-like cell lines HCT116 and HT29 were used for screening more than 500 synthetic compounds by sulforhodamine B (SRB) cell proliferation assay. The candidate compound was studied in vitro by SRB cell proliferation assay, western blotting, cell colony formation assay, quantitative real-time PCR, flow cytometry analysis, and transwell migration assay. Sphere formation assay and limiting dilution analysis (LDA) were performed for measuring the effect of compound on stemness properties. In vivo subcutaneous tumor growth xenograft model and liver metastasis model were performed to test the efficacy of the compound treatment. Student’s t test was applied for statistical analysis. Results We report the development and characterization of a small molecule inhibitor QW24 against BMI-1. QW24 potently down-regulates BMI-1 protein level through autophagy-lysosome degradation pathway without affecting the BMI-1 mRNA level. Moreover, QW24 significantly inhibits the self-renewal of colorectal CICs in stem-like colorectal cancer cell lines, resulting in the abrogation of their proliferation and metastasis. Notably, QW24 significantly suppresses the colorectal tumor growth without obvious toxicity in the subcutaneous xenograft model, as well as decreases the tumor metastasis and increases mice survival in the liver metastasis model. Moreover, QW24 exerts a better efficiency than the previously reported BMI-1 inhibitor PTC-209. Conclusions Our preclinical data show that QW24 exerts potent anti-tumor activity by down-regulating BMI-1 and abrogating colorectal CICs self-renewal without obvious toxicity in vivo, suggesting that QW24 could potentially be used as an effective therapeutic agent for clinical colorectal cancer treatment.

scholarly journals Circular RNA Hsa_Circ_0007444 Inhibits Tumor Progression Through MiR-23a-3p/DICER1 in Ovarian Cancer

2021 ◽  
Author(s):  
Min Zhang ◽  
Yu Sun ◽  
Hanzi Xu ◽  
Yaqian Shi ◽  
Rong Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cell Lines ◽  
Xenograft Model ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Ovarian Cancer Cells ◽  
Mouse Xenograft Model

Abstract Background: Circular RNAs are a class of non-coding regulatory RNAs reported to be involved in cancer development and progression. Previous studies, including our own, have indicated that hsa_circ_0007444 was downregulated in ovarian cancer (OC) tissues. Herein, we demonstrated another mechanism of hsa_circ_0007444 in ovarian cancer.Methods: The expression of hsa_circ_0007444, miR-23a-3p, and DICER1 were determined by quantitative real-time PCR. Cell proliferation, invasion, migration, and apoptosis were examined by cell counting kit 8, transwell, and flow cytometry assays. The roles of hsa_circ_0007444 in tumor growth and metastasis were assessed in vivo using a nude mouse xenograft model. The bioinformatics tools were employed to predict the binding sites, which were then verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assays. DICER1 protein level was measured by western blot. Results: Hsa_circ_0007444 was downregulated in ovarian cancer cell lines compared with normal ovarian epithelial cell lines. Also, gain- and loss-of-function results indicated that hsa_circ_0007444 inhibited cell proliferation, invasion, migration, increased cell apoptosis of ovarian cancer cells in vitro, and impaired tumor growth and lung metastasis in vivo. Additionally, the results of the bioinformatics analysis, RIP, dual-luciferase reporter, and rescue assays confirmed that hsa_circ_0007444 could interact with AGO2 and sponge miR-23a-3p, thereby upregulating DICER1 expression, which was an important tumor suppressor in ovarian cancer.Conclusion: We found that overexpressed hsa_circ_0007444 could inhibit ovarian cancer progression through the hsa_circ_0007444/miR-23a-3p/DICER1 axis.

scholarly journals A comprehensive in vivo and mathematic modeling-based kinetic characterization for aspirin-induced chemoprevention in colorectal cancer

2020 ◽  
Vol 41 (6) ◽  
pp. 751-760 ◽  
Author(s):  
Tadanobu Shimura ◽  
Shusuke Toden ◽  
Natalia L Komarova ◽  
Crichard Boland ◽  
Dominik Wodarz ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Lines ◽  
Tumor Cell Proliferation ◽  
Death Rates ◽  
Kinetics Of

Abstract Accumulating evidence suggests that aspirin has anti-tumorigenic properties in colorectal cancer (CRC). Herein, we undertook a comprehensive and systematic series of in vivo animal experiments followed by 3D-mathematical modeling to determine the kinetics of aspirin’s anti-cancer effects on CRC growth. In this study, CRC xenografts were generated using four CRC cell lines with and without PIK3CA mutations and microsatellite instability, and the animals were administered with various aspirin doses (0, 15, 50, and 100 mg/kg) for 2 weeks. Cell proliferation, apoptosis and protein expression were evaluated, followed by 3D-mathematical modeling analysis to estimate cellular division and death rates and their impact on aspirin-mediated changes on tumor growth. We observed that aspirin resulted in a dose-dependent decrease in the cell division rate, and a concomitant increase in the cell death rates in xenografts from all cell lines. Aspirin significantly inhibited cell proliferation as measured by Ki67 staining (P < 0.05–0.01). The negative effect of aspirin on the rate of tumor cell proliferation was more significant in xenograft tumors derived from PIK3CA mutant versus wild-type cells. A computational model of 3D-tumor growth suggests that the growth inhibitory effect of aspirin on the tumor growth kinetics is due to a reduction of tumor colony formation, and that this effect is sufficiently strong to be an important contributor to the reduction of CRC incidence in aspirin-treated patients. In conclusion, we provide a detailed kinetics of aspirin-mediated inhibition of tumor cell proliferation, which support the epidemiological data for the observed protective effect of aspirin in CRC patients.

scholarly journals Circ-BANP Contributes to Cell Carcinogenesis and Aerobic Glycolysis by Regulating MAPK1 Through miR-874-3p in Colorectal Cancer

2021 ◽  
Author(s):  
Yunxin Zhang ◽  
Kexin Shen ◽  
Hanyi Zha ◽  
Wentao Zhang ◽  
Haishan Zhang
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Xenograft Model ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Nuclear Antigen ◽  
Luciferase Reporter

Abstract BackgroundCircular RNA-BTG3 associated nuclear protein (circ-BANP) was identifified to involve in cell proliferation of colorectal cancer (CRC). The aerobic glycolysis is a key metabolism mediating cancer progression. However, the role of circ-BANP on aerobic glycolysis in CRC remains unknown. MethodsThe expression of circ-BANP, microRNA (miR)-874-3p, and mitogen-activated protein kinase 1 (MAPK1) mNRA was detected using quantitative real-time polymerase chain reaction. Cell viability and invasion were measured by cell counting kit-8 assay or transwell assay. Glucose consumption and lactate production were assessed by a glucose and lactate assay kit. XF Extracellular Flux Analyzer was used to determine extracellular acidifification rate (ECAR). Western blot was used to analyze the levels of hexokinase-2 (HK2), pyruvate kinase M2 (PKM2), MAPK1, proliferating cell nuclear antigen (PCNA), Cyclin D1, N-cadherin, E-cadherin, hypoxia inducible factor-1α (HIF-1α), glucose transport protein 1(GLUT1), and c-Myc. The interaction between miR-874-3p and circ-BANP or MAPK1 was confifirmed by dual luciferase reporter assay. In vivo experiments were conducted through the murine xenograft model. ResultsCirc-BANP was up-regulated in CRC tissues and cell lines. Circ-BANP knockdown suppressed CRC cell proliferation, invasion and aerobic glycolysis in vitro as well as inhibited tumor growth in vivo. Circ-BANP was a sponge of miR-874-3p and performed anti-tumor effffects by binding to miR-874-3p in CRC cells. Subsequently, we confifirmed MAPK1 was a target of miR-874-3p and circ-BANP indirectly regulated MAPK1 expression by sponging miR-874-3p. After that, we found MAPK1 overexpression partially reversed circ-BANP deletion-mediated inhibition on cell carcinogenesis and aerobic glycolysis in CRC. ConclusionCirc-BANP accelerated cell carcinogenesis and aerobic glycolysis by regulating MAPK1 through miR- 874-3p in CRC, suggesting a promising therapeutic strategy for CRC treatment.

scholarly journals Long non-coding RNA PTPRG-AS1 promotes cell tumorigenicity in epithelial ovarian cancer by decoying microRNA-545-3p and consequently enhancing HDAC4 expression

2020 ◽  
Author(s):  
Juanjuan Shi ◽  
Xijian Xu ◽  
Dan Zhang ◽  
Jiuyan Zhang ◽  
Hui Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Epithelial Ovarian Cancer ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Background: Long non-coding RNA PTPRG antisense RNA 1 (PTPRG-AS1) deregulation has been reported in various human malignancies and identified as an important modulator of cancer development. Few reports have focused on the detailed role of PTPRG-AS1 in epithelial ovarian cancer (EOC) and its underlying mechanism. This study aimed to determine the physiological function of PTPRG-AS1 in EOC. A series of experiments were also performed to identify the mechanisms through which PTPRG-AS1 exerts its function in EOC.Methods: Reverse transcription-quantitative polymerase chain reaction was used to determine PTPRG-AS1 expression in EOC tissues and cell lines. PTPRG-AS1 was silenced in EOC cells and studied with respect to cell proliferation, apoptosis, migration, and invasion in vitro and tumor growth in vivo. The putative miRNAs that target PTPRG-AS1 were predicted using bioinformatics analysis and further confirmed in luciferase reporter and RNA immunoprecipitation assays.Results: Our data verified the upregulation of PTPRG-AS1 in EOC tissues and cell lines. High PTPRG-AS1 expression was associated with shorter overall survival in patients with EOC. Functionally, EOC cell proliferation, migration, invasion in vitro, and tumor growth in vivo were suppressed by PTPRG-AS1 silencing. In contrast, cell apoptosis was promoted by loss of PTPRG-AS1. Regarding the mechanism, PTPRG-AS1 could serve as a competing endogenous RNA in EOC cells by decoying microRNA-545-3p (miR-545-3p), thereby elevating histone deacetylase 4 (HDAC4) expression. Furthermore, rescue experiments revealed that PTPRG-AS1 knockdown-mediated effects on EOC cells were, in part, counteracted by the inhibition of miR-545-3p or restoration of HDAC4.Conclusions: PTPRG-AS1 functioned as an oncogenic lncRNA that aggravated the malignancy of EOC through the miR-545-3p/HDAC4 ceRNA network. Thus, targeting the PTPRG-AS1/miR-545-3p/HDAC4 pathway may be a novel strategy for EOC anticancer therapy.

scholarly journals Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

2018 ◽  
Vol 46 (4) ◽  
pp. 1693-1703 ◽  
Author(s):  
Jianjun Chen ◽  
Yang Luo ◽  
Yong Zhou ◽  
Shaolan Qin ◽  
Yier Qiu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Expression Profile ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Extracellular Proteases ◽  
Proliferation And Invasion

Background/Aims: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. Methods: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. Results: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. Conclusion: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.

scholarly journals EIF3H promotes aggressiveness of esophageal squamous cell carcinoma by modulating Snail stability

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Xiaobin Guo ◽  
Rui Zhu ◽  
Aiping Luo ◽  
Honghong Zhou ◽  
Fang Ding ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Colony Formation ◽  
Tumor Growth And Metastasis

Abstract Background Overexpression of eukaryotic translation initiation factor 3H (EIF3H) predicts cancer progression and poor prognosis, but the mechanism underlying EIF3H as an oncogene remains unclear in esophageal squamous cell carcinoma (ESCC). Methods TCGA database and the immunohistochemistry (IHC) staining of ESCC samples were used and determined the upregulation of EIF3H in ESCC. CCK8 assay, colony formation assay and transwell assay were performed to examine the ability of cell proliferation and mobility in KYSE150 and KYSE510 cell lines with EIF3H overexpression or knockdown. Xenograft and tail-vein lung metastatic mouse models of KYSE150 cells with or without EIF3H knockdown were also used to confirm the function of EIF3H on tumor growth and metastasis in vivo. A potential substrate of EIF3H was screened by co-immunoprecipitation assay (co-IP) combined with mass spectrometry in HEK293T cells. Their interaction and co-localization were confirmed using reciprocal co-IP and immunofluorescence staining assay. The function of EIF3H on Snail ubiquitination and stability was demonstrated by the cycloheximide (CHX) pulse-chase assay and ubiquitination assay. The correlation of EIF3H and Snail in clinical ESCC samples was verified by IHC. Results We found that EIF3H is significantly upregulated in esophageal cancer and ectopic expression of EIF3H in ESCC cell lines promotes cell proliferation, colony formation, migration and invasion. Conversely, genetic inhibition of EIF3H represses ESCC tumor growth and metastasis in vitro and in vivo. Moreover, we identified EIF3H as a novel deubiquitinating enzyme of Snail. We demonstrated that EIF3H interacts with and stabilizes Snail through deubiquitination. Therefore, EIF3H could promote Snail-mediated EMT process in ESCC. In clinical ESCC samples, there is also a positive correlation between EIF3H and Snail expression. Conclusions Our study reveals a critical EIF3H-Snail signaling axis in tumor aggressiveness in ESCC and provides EIF3H as a promising biomarker for ESCC treatment.

scholarly journals miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 735 ◽  
Author(s):  
Kwang Seock Kim ◽  
Dongjun Jeong ◽  
Ita Novita Sari ◽  
Yoseph Toni Wijaya ◽  
Nayoung Jun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Xenograft Model ◽  
Mesenchymal Transition ◽  
Normal Tissues

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients.

Effect of cabazitaxel on the growth of human castration-refractory prostate cancer cells in vitro compared to docetaxel and on the anti-tumor properties of the angio-inhibitor PEDF in vivo.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 205-205
Author(s):  
Thomas Nelius ◽  
Courtney Jarvis ◽  
Dalia Martinez-Marin ◽  
Stephanie Filleur
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
In Vitro Cytotoxicity ◽  
In Vivo Studies ◽  
Raw264.7 Macrophages

205 Background: Docetaxel/DTX and cabazitaxel/CBZ have shown promise in the treatment of metastatic Castration-Refractory Prostate Cancer/mCPRC however, comparative studies are missing. Toxicities of these drugs are significant, urging the need to modify taxane regimens. Recently, low-dose metronomic/LDM treatments using conventional chemotherapeutic drugs have shown benefits in CPRC in improving the effect of anti-angiogenic agents. Previously, we have demonstrated that LDM-DTX in combination with PEDF curbs significantly CRPC growth, limits metastases formation and prolongs survival in vivo. In this study, we intended to compare the cytotoxic effect of CBZ and DTX on CRPC cells in vitro and CL1 tumors in vivo. Methods: PC3, DU145 cell lines were from ATCC.CL1 cells were obtained from androgen-deprived LNCaP cells. Cell proliferation was assessed by crystal violet staining and cell cycle analyses. In vitro cytotoxicity assays were performed on CL1 cells/RAW264.7 macrophages co-cultures treated with PEDF and increasing doses of taxanes. For the in vivo studies, CL1 cells were engineered to stably express the DsRed Express protein +/- PEDF. PEDF anti-tumor effects were assessed on s.c. xenografts treated with DTX (5mg/kg ip ev. 4 day) as reference, CBZ (5mg/kg ip ev. 4 days, 1mg/kg for 10 days, 0.5mg/kg q.a.d. and 0.1mg/kg daily) or placebo. Results: CBZ limits cell proliferation with a greater efficacy than DTX in all CRPC cell lines tested. DU145 presented the largest difference. High doses of taxane blocked tumor cells in mitosis, whereas LDM increased the SubG1 population. This effect was significantly higher in DU145 cells treated with CBZ. In vivo, 5mg/kg CBZ delayed tumor growth more efficiently than 5mg/kg DTX. PEDF/5mg/kg CBZ markedly delayed tumor growth compared to all treatments. Finally, engulfment of tumor cells by macrophages was higher in combined treatments suggesting an inflammation-related process. Conclusions: CBZ is more efficient than DTX both in vitro and in vivo.The data also reinforce PEDF as a promising anti-neoplasic agent in combination with LDM taxane chemotherapies.

scholarly journals The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway

2008 ◽  
Vol 295 (6) ◽  
pp. G1150-G1158 ◽  
Author(s):  
Sharon DeMorrow ◽  
Heather Francis ◽  
Eugenio Gaudio ◽  
Julie Venter ◽  
Antonio Franchitto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Calcium Release ◽  
Wnt Signaling Pathway ◽  
Xenograft Model ◽  
Orphan Receptor

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca2+-dependent pathway involving protein kinase C, or a Ca2+-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH2-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

scholarly journals Overexpression of PFKFB3 Promotes Cell Glycolysis and Proliferation in Renal Cell Carcinoma

2021 ◽  
Author(s):  
Jun Li ◽  
Shiqiang Zhang ◽  
Dingzhun Liao ◽  
Qian Zhang ◽  
Chujie Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Renal Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Aerobic Glycolysis ◽  
Xenograft Model

Abstract Background: Cancer cells prefer aerobic glycolysis to increase their biomass and sustain uncontrolled proliferation. As a key glycolytic activator, phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) has been implicated in the progression of multiple types of tumors. However, the specific function and clinical significance of PFKFB3 in renal cell carcinoma (RCC) remain unclear. In the present study, we explored the role of PFKFB3 in RCC.Methods: We analyzed the expression of PFKFB3 in clear cell renal cell carcinoma (ccRCC) tissues and its relationship with clinical characteristics of ccRCC. Real-time PCR and Western blot analysis were used to detect PFKFB3 expression levels in different RCC cell lines. Furthermore, we determined the glycolytic activity by glucose uptake, lactate secretion assay and ECAR analysis. CCK-8 assay, clone formation assay, flow cytometry and EdU assay were performed to monitor cancer cell proliferation and cell cycle distribution. In addition, nude mice xenograft model was used to investigate the role of PFKFB3 in tumor growth in vivo.Results: In this study, we found that PFKFB3 was significantly up-regulated in RCC tissues and cell lines compared with normal control. Overexpression of PFKFB3 was positively associated with advanced TNM stage and could predict poor prognosis of ccRCC patients. Furthermore, knockdown of PFKFB3 suppresses cell glycolysis, proliferation and cell cycle G1/S transition in RCC cells. Importantly, in vivo experiments confirmed that PFKFB3 knockdown delayed tumor growth derived from the ACHN cell line.Conclusion: Our results suggest that PFKFB3 plays an important role in the progression of RCC via mediating glycolysis and proliferation, and provides a potential therapeutic target for RCC.

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